Leiomyomas (uterine fibroids) are a major disease that affects women but remain shockingly understudied with few nonsurgical therapeutic options. Leiomyomas are characterized by excessive deposition of extracellular matrix and enhanced proliferation and tumorigenesis of uterine smooth muscle cells. Currently available treatments for leiomyomas are limited due in large part to the fact that the mechanisms regulating the development and growth of these tumors are still not well understood. We and others hypothesize that leiomyomas develop in the uterine myometrium as a response to inflammation or injury caused by local ischemia or hypoxia during menstruation or the presence of bacterial or other pathogens. We also hypothesize that dietary intervention with compounds known to inhibit inflammation-associated pathways, will decrease growth of fibroids leading to decreased size and amelioration of symptoms. We believe that dietary intervention with compounds containing high levels of omega-3 fatty acids (OM-3FA) will have a beneficial effect on leiomyomas by reducing inflammation and subsequent growth. Recently our lab has characterized oviductal leiomyomas that occur spontaneously in hens as they age as a new, relatively inexpensive, naturally occurring animal model for leiomyomas. We now have preliminary data showing that hens fed a flaxseed diet showed a decrease in size of leiomyomas compared to hens fed the normal corn-based diet. We propose to test our hypothesis in the hen model for leiomyomas with the following aim: To evaluate the efficacy of a one-year dietary intervention with regular flaxseed vs. high lignan/low omega-3 flaxseed (Linola) vs. flaxseed oil-derived omega 3 (OM-3FA) on the incidence and severity (size) of oviductal leiomyomas in aging laying hens. This will be accomplished using older hens in their 3rd year of lay in a one year feeding study in which hens will be fed one of four diets; control with 10% corn oil; 10% whole (regular) flaxseed; 5% OM-3FA; or 10% high lignin/low OM-3FA. Leiomyomas will be harvested from all birds at the end of the 12 month feeding period to determine numbers of leiomyomas/bird, numbers of birds with leiomyomas, and size of leiomyomas. We will also assess a number of surrogate endpoints in leiomyomas including changes in expression of cyclo- oxygenase (COX) and prostaglandin synthase enzymes, prostaglandin levels in leiomyomas, expression of fibrotic genes and matrix proteins, proliferation/apoptosis indices, and measures of oxidative stress. The long term goal of this research is to develop clinical trials for dietary intervention in women with leiomyomas. The proposed aims will advance our knowledge of this highly prevalent public health challenge for which treatment options are currently limited at best. The proposed work is scientifically, translationally, and clinically significant because it provides a new perspective on and better understanding of the mechanisms underlying leiomyoma development and opens up possibilities for identifying additional therapeutic targets and strategies.